The present invention relates to immunosuppressive agents for the control or prophylaxis of neurological disorders such as multiple sclerosis, and for use in the field of organ and other tissue transplants.
It has been established that administration of linoleic acid (9,12-octadecadienoic acid) has an immunosuppressive effect on the lymphocyte-antigen reaction which has a destructive effect on the protective myelin sheath of the nervous system and is believed to be the factor responsible for relapses in multiple sclerosis. Large doses of vegetable oils rich in linoleic acid such as sunflower oil and safflower oil have been administered to subjects suffering from multiple sclerosis and it has been found that this treatment does lead to a reduction in the frequency and severity of relapses.
However it is thought that the consumption of large doses (for example 4 tablespoons) of vegetable oil daily over a prolonged period, frequently for several years, can lead to undesirable side effects. Firstly the swallowing of large quantities of oil can produce nausea. Secondly a large intake of linoleic acid can give rise to high levels of linoleic acid in the blood-stream where it is susceptible to auto-oxidation with the formation of peroxides and possible combination with free radicals to form toxic products. Finally vegetable oils such as sunflower oil and safflower oil contains a varying content of linolenic acid (9,12,15-octadecatrienoic acid) which, if the daily intake reaches 0.1% of the total dietary calories, can block the normal metabolic elongation of linoleate to arachidonate (5,8,11,14-eicosatetraenoate), the latter being an important component of the myelin sheath.
There is thus a need for a new treatment for multiple sclerosis which avoids the necessity for the consumption of large quantities of vegetable oils containing high levels of linoleates but which serves to maintain an adequate level of arachidonates in the body.
There is also a need for immuno-suppressive agents for use in the control or prophylaxis of neurological disorders generally and in the transplanting of organs and other tissues from a donor to a recipient patient. Thus the control of various stages of the immune response is of major importance in transplantation of organs and other tissues.
British Patent Specification No. 896,903 (Calmic Ltd). describes and claims pharmaceutical compositions containing linoleic acid and arachidonic acid for use in the prevention and treatment of atheromic conditions and in particular atherosclerosis. Although the mode of action of arachidonic acid is not known, it has been found that arachidonic acid lowers the cholesterol level in the blood, a high blood cholesterol level being a symptom of atherosclerosis.
British Patent Specification No. 1,802,624 (Calmic Ltd.) discloses the effectiveness of .gamma.-linolenic acid (6,9,12-octadecatrienoic acid) in the treatment of vascular diseases and claims therapeutic compositions containing .gamma.-linolenic acid and its derivatives and in particular an oil extracted from the seeds of the Evening Primrose (Oenothera biennis L.) which is rich in the triglyceride of .gamma.-linolenic acid. It is known that .gamma.-linolenic acid is an important intermediate in the metabolism of linoleic acid to arachidonic acid and it has been found that while only a part of any linoleic acid which is administered is converted to arachidonic acid, almost all .gamma.-linolenic acid administered to living tissue is rapidly converted to arachidonic acid. It has further been found that during the onset of illness which is accompanied by abnormal lipid metabolism the conversion of linoleic acid to .gamma.-linolenic acid is inhibited and this is thought to be a factor in the fall of the arachidonic acid level.
British Patent Specification No. 1,240,513 (Ono Pharmaceutical Co., Ltd.) describes and claims therapeutic compositions for the treatment of atherosclerosis containing as active ingredient at least 30% by weight of the methyl or ethyl ester of .gamma.-linolenic acid. A process for the preparation of the compositions is described which comprises up-grading the .gamma.-linolenic acid content of seed oil extracted from seeds of the Oenothera species (which normally contains about 7 to 26% of .gamma.-linolenic acid) by treatment with urea.